Antibody-DrugConjugates:APrecision DeliveryRevolutionAgainstCancer

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Antibody–drugconjugates(ADCs)representarevolutionarytargetedanticancertherapythat combineshigh-specificitymonoclonalantibodieswithpotentcytotoxicagentsviacleavableornoncleavablelinkers,achievingprecisiondrugdeliveryakintoPaulEhrlich’s“magicbullet”concept [1].ThisreviewsystematicallytracestheevolutionofADCtechnologyacrossthreegenerations: fromfirst-generationagents(e.g.,gemtuzumabozogamicin)thatencounteredsetbacksdueto immunogenicityandlinkerinstability,throughsecond-generationagents(e.g.,brentuximab vedotin)thatachievedclinicalsuccessviahumanizedantibodies,morestablelinkers,andmore potentpayloads,tothird-generationagents(e.g.,trastuzumabderuxtecan)thatleveragesite-specific conjugation,novelpayloads(e.g.,pyrrolobenzodiazepinedimers),andbystanderkillingeffectsto achievebreakthroughsinefficacyandindications.Thereviewfurtheranalyzesclinicalchallenges includingtumorheterogeneity-driven drugresistanceandon-target/off-tumortoxicity, andtracks emergingtechnologiessuchasantibody–bottlebrushprodrugconjugates(ABCs)andbispecific nanobody–drugconjugates.Finally,wediscussfuturedirectionsintargetexpansion,combination therapy,andnon-oncologicalapplications.

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